A noninvasive optical imaging technology can detect and quantify retinal amyloid deposits in living patients with Alzheimer’s disease, according to a recent proof-of-concept clinical trial. The aggregation of misfolded amyloid β-protein is a hallmark of Alzheimer’s disease, but existing brain imaging tools are difficult to adapt to screen large numbers of people in clinical settings and predict disease progression. As reported in August in the journal JCI Insight, the retinal imaging approach may offer a sensitive yet inexpensive method for screening populations at risk for Alzheimer’s disease, assessing disease progression and monitoring responses to therapy.

“This is the first study to show the feasibility of detecting amyloid plaques in the retina of live patients,” said senior author Maya Koronyo-Hamaoui, an associate professor of neurosurgery and biomedical sciences at Cedars-Sinai Medical Center in Los Angeles, California. “With the imaging technology’s ability to detect the autofluorescence signal related to retinal amyloid β-protein, these findings may lead to a practical approach for large-scale identification of the at–risk population and monitoring of Alzheimer’s.”

Alzheimer’s disease is the most common cause of dementia among older adults and a leading cause of death in the United States. Remarkably, amyloid β-protein can accumulate in the brain as early as 20 years before the onset of clinical dementia. The ability to noninvasively detect early-stage disease with high specificity and sensitivity could greatly facilitate the identification of at-risk populations for earlier, more effective intervention. However, existing brain amyloid-imaging tools pose a number of challenges, including high costs, limited availability, and exposure to radioactive isotopes.

“Current AD [Alzheimer’s disease] biomarker tests are either highly invasive, requiring cerebrospinal fluid collection, or are expensive and labor-intensive, as in the case of neuroimaging, making them unsuitable for use in the primary care, clinical office-based setting or to assess drug efficacy in clinical trials,” said Tapan Khan, a lead research scientist at the Blanchette Rockefeller Neurosciences Institute at West Virginia University who was not involved in the new study.

To address this issue, Koronyo-Hamaoui and her team turned their attention to amyloid pathology in the retina—a tissue readily accessible for direct, noninvasive imaging at high resolution and low cost—to define at-risk populations for further clinical evaluation with gold-standard brain imaging. In a previous study, the researchers identified amyloid-β plaques in postmortem retinas from Alzheimer’s patients and in suspected early-stage cases. They also developed a noninvasive retinal amyloid imaging method for rodent models of Alzheimer’s disease, using a natural and safe plaque-labeling fluorochrome called curcumin as an amyloid contrast agent.

In the new study, Koronyo-Hamaoui and her team demonstrated the feasibility of their retinal optical imaging approach in living humans. Ten patients with mild-to-moderate Alzheimer’s disease and six control subjects took part in the clinical study. The participants received oral curcumin for either two or 10 days, and their retinas were imaged throughout the experiment using a scanning laser ophthalmoscope. Based on these images, the researchers calculated the retinal amyloid index (RAI)—a quantitative measure of increased curcumin fluorescence. Analysis of RAI scores showed more than a two-fold increase in Alzheimer’s patients compared with controls.

The findings suggest the utility of noninvasive retinal amyloid plaque imaging as a surrogate biomarker of Alzheimer’s disease. “If a link between specific changes in the retina and a brain disease can be established by further extended research, an eye examination can help to identify an early sign for AD or other brain diseases to facilitate development of therapeutic invention for both prevention and treatments,” said Zhiqun Tan, an associate research professor of neurology at the University of California, Irvine who was not involved in the study.

But larger follow-up studies are needed to assess the ability of the RAI score to detect the disease with high sensitivity and specificity, and to determine whether retinal amyloid burden is a reliable biomarker. “Frankly, there is still a long way to put these findings to use in clinical practice, as there is still a long list of questions that should be answered,” Tan said. “Future research needs to examine whether AD-related lesions in the retina are specifically or directly correlated with brain damage or cognitive dysfunction, that is, the severity of dementia. It is equally important to determine whether curcumin-based retinal imaging can detect early stage AD-lesions, particularly in people with normal MMSE [Mini Mental State Examination] scores or mild cognitive impairment.”